Korean Circ J.  2012 May;42(5):295-301. 10.4070/kcj.2012.42.5.295.

Mechanisms of Platelet Activation and Integrin alphaIIbeta3

• Joo SJ

• KMID: 2028756
• DOI: http://doi.org/10.4070/kcj.2012.42.5.295

Abstract

Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane A2 activate platelet integrin alphaIIbbeta3 through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by Gq, G12/G13 or Gi, include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin alphaIIbbeta3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of beta3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate.

Keyword

Platelet activation; Receptors, G-protein-coupled; Integrin alpha-IIb beta-3

MeSH Terms

Acute Coronary Syndrome
Adenosine Diphosphate
Blood Platelets
Calcium Signaling
Cytoplasm
Fibrinogen
Guanine Nucleotide Exchange Factors
Hemostasis
Ligands
Phosphatidylinositol 3-Kinase
Platelet Activation
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Kinase C
Proteins
Receptors, G-Protein-Coupled
Stroke
Thrombin
Thromboxane A2
Type C Phospholipases
von Willebrand Factor
Adenosine Diphosphate
Fibrinogen
Guanine Nucleotide Exchange Factors
Ligands
Phosphatidylinositol 3-Kinase
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Kinase C
Proteins
Receptors, G-Protein-Coupled
Thrombin
Thromboxane A2
Type C Phospholipases
von Willebrand Factor

Figure

• 

  Fig. 1 ADP receptors in the platelet. ADP binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelets shape. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of Gi-coupled P2Y12 receptor inhibits protein kinase C, and activates phosphatidylinositol 3-kinase, resulting in the activation of GP IIb/IIIa receptors and firm platelet aggregation. P2Y12 receptors are inhibited by ticlopidine or clopidogrel. AC: adenylyl cyclase, ADP: adenosine diphosphate, cAMP: cyclic adenosine monophosphate, GP: glycoprotein, PI3K: phosphatidylinositol 3-kinase, PLC: phospholipase C, PKC: protein kinase C.

• 

  Fig. 2 A schematic structure of platelet integrin αIIbβ3. The αIIb subunit is composed of a heavy and a light chain. The light chain contains a cytoplasmic tail, a transmembrane helix, and an extracellular segment that is disulfide linked to the heavy chain, which is entirely extracellular. The β3 subunit is a single polypeptide chain. The 2 subunits assemble into the divalent, cation-dependent heterodimer.

• 

  Fig. 3 "Inside-out" and "outside-in" signaling of integrin αIIbβ3. A: platelet adhesion to extracellular matrix, or agonists, such as ADP, thrombin, or arachidonic acid, initiate platelet activation process that requires transmission of information from within the cell to the extracellular domain of αIIbβ3, a process referred to as "inside-out" signaling, which changes receptors from a low- to high-affinity state. B: ligand-occupied integrin αIIbβ3 triggers various cellular processes within platelets, through "outside-in" signaling.

• 

  Fig. 4 Molecular mechanisms involved in the activation of integrin αIIbβ3. G protein-mediated signaling pathways, which are initiated by Gq or Gi, include phospholipase C with calcium signaling, protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI-3K). Rap1b, Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), Rap1-GTP-interacting adaptor molecule (RIAM), and Akt are important molecules involved in G protein-mediated activation of integrin αIIbβ3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. AC: adenylyl cyclase, CRAC: Ca2+ release activated calcium channel, ER: endoplasmic reticulum, GSK: glycogen synthase kinase, IP3: inositol 1,4,5-triphosphate, IP3R: IP3 receptor, NOS3: nitric oxide synthase 3, PDE: phosphodiesterase, PIP2: phosphoinositol biphosphate.

• 

  Fig. 5 Mechanism of action of platelet glycoprotein (GP) IIb/IIIa blockers. Activated GP IIb/IIIa binds to fibrinogen at high affinity. Fibrinogen acts as a bridge between adjacent platelets, forming firm platelet aggregates. GP IIb/IIIa receptor antagonists inhibit fibrinogen binding to the receptors.

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